This invention relates to a process for the preparation of loweralkyl 2-(N-R'-pyrryl)-.alpha.-loweralkanoic acid esters and more particularly for the preparation of loweralkyl 2-(N-methylpyrryl) acetic acid esters, and to promoting agents used in this process.
Loweralkyl 2-(N-R'-pyrryl)-.alpha.-loweralkanoic acid esters comprise a very useful class of compounds, being intermediates for the preparation of phenothiazine derivatives (see, for example, British Pat. No. 823,733 to F. P. Doyle and M. D. Mehta) and for the synthesis of the well-known anti-inflammatory agent tolmetin and its analogs (see, for example, U.S. Pat. No. 3,752,826), and are represented by the following generic formula: ##STR1## wherein R is loweralkyl, R'is a member selected from the group consisting of hydrogen and primary loweralkyl, and R" is a member selected from the group consisting of hydrogen and loweralkyl.
The prior art method for the preparation of compounds of this type is by the decomposition of a loweralkyl .alpha.-diazoloweralkanoate, formula (II), in the presence of an N-R'-pyrrole, formula (III), with copper bronze as a catalyst or promoting agent. See, for example, H. Rapoport and E. jorgensen, J. Org. Chem., 14, 664(1949). The term "promoting agent" is used herein to mean a material which effectuates or facilitates a chemical reaction even when employed in a much less than stoichiometric amount (i.e., which functions as a catalyst, in the usual sense of the term, but which may be chemically altered in the course of the reaction). Given the chemical modification of the promoting agent, it necessarily differs from a true catalyst, which by definition remains unchanged by the reaction that it induces.
It has recently been discovered that this prior art preparative procedure does not yield only the desired 2-isomer but also yields some of the 3-isomer, formula (IV), as a by-product. This prior art process is illustrated by the following: ##STR2## wherein R, R' and R" are as previously defined.
As these two isomers are practically inseparable, it is desired to have a process whereby one obtains a reaction product as enriched as possible in the desired 2-isomer (as "pure" as possible). As used herein, the term "pure" refers specifically to the degree of enrichment in the favored 2-isomer (i.e., to the relative amount of the desired 2-isomer compared to the undesired 3-isomer). The greater the ratio of 2isomer to 3-isomer, the more "pure" the product mixture is said to be. Throughout the present application, this "purity" will be represented as the percent of the total amount of loweralkyl (N-R'-pyrryl)-.alpha.-loweralkanoic acid ester which is the desired 2-isomer.
It is also desirable to have a process which produces as much of the desirable 2-isomer as possible, regardless of the purity thereof. This characteristic will be referred to as the "yield" of the reaction and will be based upon the limiting reagent loweralkyl .alpha.-diazoloweralkanoate.
The prior art procedure is less than desirable in both the purity and the yield of the product. For example, the prior art preparative method for N-methylpyrrole acetic acid ethyl esters generally produces a product mixture having a purity of about 82% of the desired 2-isomer and a yield of the desired 2-isomer of about 32%, based on the ethyl diazoacetate. It should be noted at this point that, for this particular product, the literature often reports yields based upon N-methylpyrrole rather than ethyl diazoacetate; these yields appear considerably larger than those as calculated herein because they are not based upon the limiting reagent, ethyl diazoacetate. For valid comparision of two percentage yields, they must both be based on the same starting material. Throughout this application all yields are based on the amount of loweralkyl .alpha.-diazoloweralkanoate consumed in the reaction.
It is known in the chemical art that the effect of different types of catalysts on an individual reaction, or on related reactions, is very difficult to predict. A given catalyst may be ineffective in one reaction, while being the catalyst of choice in a closely related reaction. Different catalysts may result in different products or different ratios of products from the same starting materials. This unpredictability with respect to copper catalysts in diazo compound reactions is discussed, for example, on page 251 of "The Reaction of Diazoacetic Esters with Alkenes, Alkynes, Heterocyclic and Aromatic Compounds", Chapter 3, in Organic Reactions, 18, 217 (1970), by V. Dane and E. W. Warnhoff.
It has now surprisingly been discovered that the yield of the desired 2-isomer can be significantly increased and, in some case, the purity of the product improved through the use of the copper (II) 1,3-diketonate, copper (II) salicylaldehyde, copper (II) monoamino-1,3-diketonate, and copper (II) salicylaldimine complexes of the invention as promoting agents.